New use of polymeric membranes in the dispensing of pharmaceutical solutions that contain quaternary ammonium compounds as preservatives and corresponding dose dispensor

Abstract: Said use is characterized in that the cited membranes are placed adequately in the dropper of the dose dispensor and are used to achieve the selective flow of essentially all the active product and the selective retention of essentially all the preservative during pharmacological treatment. The membrane (5) is coupled between the cylinder units (6 and 7) of parts (3 and 4) of the dropper, remaining in a movable position (Figure 3) thanks to the existence of a certain play between said cylinder units; or else, in a fixed position (Figure 4) due to the lack of said play; or else, in a fixed position but with the membrane treated adequately, so that it has a small area or "stain" that permits the flow of air; (8) represents the outlet duct.

Description: The invention relates to a new use of polymeric membranes in the dispensing of pharmaceutical solutions that include a quaternary ammonium compound as a preservative. The invention also refers to a new container that includes one or several membranes of polymeric material, preferably polyvinylidene fluoride (PVDF) or polysulfone, capable of selectively retaining, when applied the quaternary ammonium compounds, preferably benzalkonium chloride (BAC), or benzethonium chloride (BTC), that pharmaceutical solutions include as a preservative permitting the free flow without retention of the active principles. The need to include in pharmaceutical solutions, particularly ophthalmic solutions, that are to be applied in successive doses elements that are capable of preventing or limiting therein the growth of micro-organisms that can contaminate the patient when he uses them, preventing greater harm than that whose alleviation is sought, is known. All the excipients of the formulation that are used for this cited purpose are called preservative systems. A group of substances that are used as a preservative system due to their broad antimicrobial spectrum are quaternary ammonium compounds. From a chemical point of view, the quaternary ammonium compounds used are products resulting from the reaction of an organic halide, preferably a chloride or a bromide, with a tertiary amine. The chemical structure that they have is the following: wherein R 1 , R 2 , R 3 and R 4 are: alkyl, alkylene, alkyl or aryl groups; identical or different; substituted or unsubstituted; branched or unbranched; cyclic or linear; that main contain ether, ester or amide bonds; and X is the corresponding halide. Within the compounds belonging to this group that are included in pharmaceutical formulations as the preservative system, benzalkonium chloride, benzethonium chloride, benzodecinium bromide, cetalkonium chloride, cetexonium bromide, cetrimide and cetylpyridine, among others, stand out. The concentrations of quaternary ammonium compound that are normally used in pharmaceutical solutions vary between 0.0005% and 1.0%, depending on the rest of the components of the formulation. Said quaternary ammonium compounds, have the characteristic, just like other cationic surface active agents, of interacting with different polymeric materials (Saito and Yukawa (1969), Naidoo et al. (1971), Richardson et al. (1979); Goddard (1986.)) Said interaction causes difficulties in the handling and storage of preparations that contain quaternary ammonium compounds and that have to come in contact with polymeric materials. On the other hand, the concentrations of quaternary ammonium compounds that are needed to be reached to ensure the antimicrobial effect can, in some cases, give rise to undesirable side effects. Among others, corneal de-epithelization, modification of the scarring of the cornea, modification of the electrophysiology of the corneal membrane and of the oxygenation of the cornea can be pointed out. Said effects can be increased depending on the pathological state of the cornea and can have a greater repercussion on the patient who has to be subjected to chronic treatment, such as antiglaucomatous treatments. Said side effects can affect the bioavailability of the active principle that the pharmaceutical solution includes. Different researchers have tried to minimize the cited effects from the point of view of the container. The main solutions proposed are the following ones: 1. The system described in Spanish industrial model no. 99011 "Group of containers of a dosed content" and in Spanish utility model 257316 "Group of containers-eye droppers of a dosed content" consists of a container that contains the necessary amount of the solution, preservative-free, for a single application discarding the same after use thereof. This system has the inconvenience that it has to be made in perfectly sterile conditions, since if there is any contamination at the moment of initial packaging, or subsequently inside the monounits and as there is no preservative, said contamination cannot be counteracted. Another limitation is the need to make the user aware that once a unit has been used, it should be discarded, though there is a residual volume left. As an economic restriction, the high price of each unit with regard to the conventional multidose system stands out. 2. Systems described in EP-A-0401022 (US-A-5265770) Matkovitch et al. "Contamination-Resistant Dispensing and Metering Device" and US-A-4463880 Kramer et al. "Medicine Drop Dispenser with Anti-Bacterial Filter" that consist preventing contamination entering the inside of a container, that contains a preservative-free solution, by means of use of reduced pore size filters. This system has the advantage of ensuring sterility of the liquid instilled even when the latter is contaminated, due to the solution being filtered again before coming out of the container. The inconveniences of this option are in the first place the poor appearance that a contaminated solution may have and the relatively high force that the filter offers due to the small size of the pores. Besides, the filters do not allow air to enter, which implies a gradual contraction of the container, as the amount of product applied increases. These inconveniences make industrialization and marketing of this system difficult. 3. FR-A-2661401 Chibret et al."Procédé de conditionnement pour conserver et distribuer par portions du liquide stérile", consists of placing in the end of the container a column that selectively retains the preservative and not the active principle. As a main inconvenience the need to design a column for each family of active principles and preservatives, which results very complicated and burdensome is worth pointing out. Consequently, the price of each unit turns out to be very high. Besides, the container must be able to contract, for the above cited reasons. 4. In US-A 4846810 Gerber et al. "Valve Assembly," US-A-5074440 Clements et al. "Container for dispensing Preservative-Free Preparations and US-A-5373971 (U.S. Patent Application No. 563504) to Laffy "Aseptic Bottle," different mechanisms of the valve or seal type, that try to dose a preservative-free solution, not permitting outside contamination to enter, can be observed. An inconvenience that they have is the incapacity to eliminate contamination present in the liquid that they contain. Another disadvantage of these alternatives is the high cost of each unit, the difficult industrialization thereof, as well as the significant task of informing the user who requires them. This container must also prevent the contraction thereof, due to the principal of its operation. The cited solutions do not satisfactorily solve the posed problem, thus, it is still necessary to find a system that permits quaternary ammonium compounds to be present in the formulation of the pharmaceutical solution, to ensure that pathogenic microorganisms cannot grow therein during the time of storage and use, and on the other hand, that the concentration of the preservative that reaches the patient in applying the solution is low enough so as to eliminate, or minimize the above mentioned side effects. EP-A-0 439 999 relates to an apparatus for removing preservatives, such as quaternary ammonium compound preservatives, from solutions, especially from ophtalmic solutions. The preservatives are removed by selective retaining means, capable of retaining the preservative but permitting the active product to pass through said retaining means. EP-A-0 439 999 discloses, as suggested examples of such selective retaining means, scavenging materials provided within the path or within the fitment. According to EP-A-0 439 999, said scavenging materials may have a positive charge for scavenging negatively charged preservatives, or a negative charge for scavenging positively charged materials, or may be materials which selectively scavenge components by a size exclusion mechanism, or may comprise any other means for removing a component from solution. Nowhere in EP-A-0 439 999, the use of a polymeric membrane as a "scavenging material" is mentioned or suggested. FR-A-2 422 569 discloses the use of filters for the purpose of preventing bacteria from entering a medicine container from the outside. WO-A-92/09 523 also discloses the use of filters for preventing bacteria from entering a medicine container. The present invention as claimed proposes to achieve the above cited aim. The container includes membranes that are capable of retaining the quaternary ammonium compounds at the moment of application. The device described in the present invention is to be coupled to the container that contains the pharmaceutical solution with quaternary ammonium compounds. In this way the preservative system can carry out its function during the time of storage and use of the same, whereby it is ensured that no microorganisms will grow in the solution, but it will be retained totally, or partially, upon passing through the membrane, or membranes, of the container at the moment of application reaching the surface to be treated a concentration of quaternary ammonium compound low enough so as to minimize the undesirable side effects of the cited compounds. In particular, the materials that the container can include are commercial membranes of cellulose triacetate, cellulose nitrate, regenerated cellulose, nylon, PVDF, silicones, polysulfone, polycarbonate, among others. The thickness of the membranes, the number, the pore size of the same and in short the area of filtration of the same will depend on the nature of the formulation to be used and the percentage of retention of quaternary ammonium compounds that is desired to be given to the container. To ensure the optimum use of the container, the membrane, or membranes, will have to be located in the outlet end, or dropper, of the dose dispenser. The present invention proposes a way how to place the membrane or membranes in the dropper of the dose dispenser. Said way, which we will call "movable filter", is based on the membrane having a possibility of movement as a result of the existence of a certain play between the cylinder units (Fig. 3) in such a way that when the liquid returns to the preservation area of the dropper a vacuum is produced (since one part of the liquid has been supplied outside) and, consequently the membrane moves downward, permitting air to flow inside the preservation area thus preventing the container from wrinkling and that, as the following successive doses are administered, it be necessary to press harder each time the dose dispenser to achieve the application of the corresponding dose of the pharmaceutical solution. The proposed way ensures that the pharmaceutical solution that has not been applied, but which goes beyond the membrane, goes back inside the container. In the event that this return does not take place and it remains retained in the outside of the dropper, it would be susceptible to contamination without the preservative system being able to act. It has been verified that the percentage of retention of the preservative, is somewhat lower than what is desired, it being possible to improve the same upon reducing the concentration of the quaternary ammonium compound and simultaneously increasing the diameter of the membrane or membranes in order to optimize the dispersion of the flow through the same. This can be achieved by changing the structure of the dropper in its connection to the neck of the container of the product, upon the bottom body of said dropper remaining fastened to the container by the outside of the neck and in such a way that the membrane or membranes that define the filtering unit can have a larger diameter even that of the mouth itself of the container. Besides, the distribution of the cylinders or support projections of the filtering membrane or membranes is improved, so that the product extends easily over the entire surface of the membrane and thus passes through it more easily, avoiding in turn the possibility that the same be perforated if a strong pressure of supply is exerted, or unless it deteriorates prematurely. The support projections for the membrane can be materialized by small finger-type cylinders, distributed preferably in concentric annular alignments. The small cylinders that surround the axial opening for flow of the product from the main body to the container have their free edges joined by means of a disk-shaped partition, of the same or different material, defining a small radial diffusion chamber given that the flow of the product in an axial direction is prevented, thus this small disk acts as a deflecting element. In the top part of the dropper, or top body of the same, there are also these support fingers of the membrane, with an identical distribution and the innermost ones having their ends likewise joined by another small disk, of an identical function and which on the other hand does not interfere with the outflow of the pharmaceutical solution. All this plurality of support projections for seating the filtering membranes can also be achieved upon providing a plurality of concentric annular partitions equidistant to each other, there being some radial or diametric cuts that form in the same passage or intercommunication ducts between the chambers formed between said annular partitions, thus obtaining a good dispersion of flow through the entire surface of the membrane. There may also be other radial channels that start in the outside part and that do not reach the center, precisely to shorten the length of the partitions The bottom body of the dropper is the element which can include the inside thread for connection to the neck of the container, having on its bottom end the sealing ring. It is also provided for that it is not necessary to include the cited thread and that this bottom body of the dropper were to fit by pressure on the neck of the container, though the corresponding sealing ring were included. The outlet mouth of the curative product, formed in the top part of the dropper, advantageously includes an outside thread for anchoring a small sealing cover of said mouth, likewise provided with a sealing ring that remains locked in the corresponding toothing provided for opposite the dropper. In order to provide a better understanding of the features of the invention and forming an integral part of this specification, some sheets in whose figures, the following has been represented in an illustrative and non-restrictive manner are attached hereto. Figure 1 represents an exploded and section view of a dose dispenser that includes the filtering membrane or membranes used in the present invention. Figure 2 represents the position of assemblying the dose dispenser of Figure 1, without including the thread cap. Figure 3 represents a larger scale sectioned view of the dropper and the "movable filter". Figure 4 represents a larger scale sectioned view of a dropper with a "fixed filter" (not claimed) Figure 5 is an exploded view of a further dose dispenser of pharmaceutical solutions (not claimed). Figure 6 is a view of the same container of figure 5, totally assembled and with the cover of the supply mouth without the seal. Figure 7 is an exploded view of the dropper wherein the two component bodies thereof and an intermediate filtering membrane are observed on a larger scale. Figure 8 is a view identical to figure 4, assembled and with an enlarged detail to show the axial structure of the support projections of the membrane, preventing the direct flow of the product outwards. In Figures 1 and 2 one can see a dose dispenser included in the present invention. As can be seen, said container has a container (1) of a material easily deformable by pressure, a thread cap (2) with its corresponding sealing ring, a dropper divided in two parts, a bottom one (3) and another top one (4) and, finally the membrane or membranes (5) that are located between the cited two parts (3) and (4) of the dropper. Hereinafter two embodiments and a variant are described in terms of the arrangement of the membrane/membranes, in the dropper of the dose dispensor: "Movable filter" embodiment (an embodiment of the dose dispenser as defined in claim 10) In view of the commented Figure 3, one can see how the membrane (5) is located between the cylinder units (6) and (7) of the bottom (3) and top (4) parts of the dropper respectively. Between both cylinder units there is a certain separation or play, whereby the membrane can move in the corresponding free space. In this way, when pressure is exerted on the container (1) of Figures 1 and 2, the pharmaceutical solution contained in the same rises through the inside cylindric part of piece (3) of the dropper, until the center hole is reached; at this point, the pressure of the liquid makes the membrane rise until it comes in contact with the top cylinder unit, filling the entire space that remains free and spreading around the entire surface of the membrane. The liquid that passes through the membrane substantially preservative-free, rises through the inside center reverse truncated-cone shaped cavity (8) of the top part (4) of the dropper until the outside. Upon the pressure exerted on the container (1) ceasing, the air itself that enters through the center hole (8) of the top part (4) to counteract the vacuum produced by the liquid removed, pushes the membrane downward which remains supported on the bottom cylinder unit of part (3) of the dropper, leaving a cavity through which the liquid retained in the duct (8) spreads again through the membrane and between the spaces existing between the cylinders (6 ), going back inside the container for its preservation. In this way, the container recovers its initial shape and no liquid remains in the top part of the dropper which could be easily contaminated upon being substantially preservative-free. The operation described is repeated as many times as necessary during the patient's treatment with a total guarantee of preservation and easy application. "Fixed filter" embodiment (this embodiment does not fall into the scope of claim 10) In view of Figure 4 one can see how the membrane (5) is located between the cylinder units (6) and (7) of the bottom (3) and top (4) parts of the dropper respectively. Between both cylinder units there is a separation just to couple the membrane, which remains fixed between both without the possibility of any type of movement or displacement. In this way when pressure is exerted on the container (1) of Figures 1 and 2, the pharmaceutical solution contained in the same rises through the cylindric inside part of piece (3) of the dropper until the center hole is reached where the liquid spreads through the cavities existing in the cylinder unit (6) to pass through the membrane on its entire surface, spreading the liquid already preservative-free through the cylinder unit (7) and rising through the inside center reverse truncated-cone shaped cavity (8) of the top part (4) of the dropper to the outside. With this embodiment, the container (1) is susceptible to contract but there is no danger of contamination of the solution. "Fixed filter with stain" embodiment (this embodiment does not fall into the scope of claim 10) The assembly and embodiment of this variant is identical to the previous one "fixed filter", only that there is a special treatment of a small part of the membrane or "stain" which permits air to flow through, thus avoiding the possible contraction of the container. Making special reference to figures 5 to 8, we can see show the dose dispensor of pharmaceutical solutions that the invention proposes, includes the improvements referred to regarding the structure of the container. Now then, the new dose dispensor that is proposed includes a dropper generally referred to as number (9), whose bottom body (10) includes an annular flap (11) that immobilizes the neck (12) of the container (1), including the sealing ring (13) that immobilizes the sawtoothing (14) of the neck of the container (1.) As we have said above, it is even possible to omit the thread since the bottom body can remain directly anchored by pressure and insertion. The top body of the dropper (9) is referred to as number (15) and its dose mouth remains closed with the sealing cap (16) upon including a thread (17.) Between bodies (10) and (15) of the dropper there is the membrane (18) whose diameter is notably larger than that which the membrane (5) may have in the structure of the dropper to which we have reffered in figures 1 to 4. In the enlarged detail of figure 8 we can also see how the membrane (18) remains fastened in this preferred embodiment, between the projections (19) of axial direction, emerging from respective recessed surfaces (20) and (21) of the proximate bases of both top (15) and bottom (10) bodies of the dropper (9), respectively. Such projections are formed as concentric annular partitions that have a discontinuous arrangement in each annular alignment, upon there being radial or diametric cuts or channels to permit easy distribution of the product towards the entire surface of the filtering membrane (18) from the axial access hole (22), just as the arrows of this figure 8 indicate. In order to prevent if too much pressure is exerted on the container (1) the product from going a totally axial direction upon the hole (22) of the bottom body (10) of the dropper being aligned with the conical outlet hole (23) of the product towards the outside, just as we had indicated before, it has been provided for that, in this embodiment shown in the figures, this direct path that could end up damaging the membrane (18) and even breaking it, is intercepted upon providing in this passage area some small horizontal partitions (24), as circular covers of the same material as the respective body of the dropper, establishing contact in this embodiment, with the membrane or membranes (18). These disks (24) close the discontinuous periphery of the free edges of the projections (19) located in the innermost annular partition. In figures 5 and 6 we see the sealing cap (16) also provided with a sealing ring (25.) The present invention is additionally illustrated by means of the following representative Examples, which must not be considered as a limitation of the scope of the same, made with a dose dispenser of the type shown in figures 1 to 4: Example 1: A study of the retention of preservative of a solution that contained 0.5% thymolol maleate and 0.1 % benzalkonium chloride. A commercial membrane of PVDF of 0.45 µm and 13 mm ⊘ had been included in the container. The percentage of benzalkonium chloride retained at the end of application of 5 ml. of the cited solution was 76%, without observing any retention of the active principle. Example 2: A study was conducted on the retention of preservative of a solution that contained 2% carteolol hydrochloride and 0.005% benzalkonium chloride. A commercial membrane od PVDF of 0.22 µm and 13 mm ⊘ had been included in the container. The percentage of benzalkonium chloride retained at the end of the application of 5 ml. of the cited solution was 100%, without observing any retention of the active principle. Example 3: A study was conducted on the retention of preservative of a solution that contained 20% pilocarpine chloride and 0.01 % benzalkonium chloride. A commercial membrane of PVDF of 0.45 µm and 13 mm ⊘ had been included in the container. The percentage of benzalkonium chloride retained at the end of the application of 5 ml. of the cited solution was 76%, without observing any retention of the active principle. Example 4: A study was conducted on the retention of preservative of a solution that contained 0.5% thymolol maleate and 0.01% benzalkonium chloride. A commercial membrane of PVDF of 0.2 µm and 13 mm⊘ had been included in the container. The percentage of benzalkonium chloride retained at the end of the application of 5 ml. of the cited solution was 90%, without observing any retention of the active principle. Example 5: A study was conducted on the retention of preservative of a solution that contained 4% sodium chromoglycate and 0.1% benzalkonium chloride. A commercial membrane of PVDF of 0.45 µm and 13mm⊘ had been included in the container. The percentage of benzalkonium chloride retained at the end of the application of 5 ml. of the cited solution was 45%, without observing any retention of the active principle. Example 6: A study was conducted on the retention of preservative of a solution that contained 4% sodium chromoglycate and 0.01% benzalkonium chloride. A commercial membrane of PVDF of 0.22 µm and 13mm⊘ had been included in the container. The percentage of benzalkonium chloride retained at the end of the application of 5 ml of the cited solution was 48%, without observing any retention of the active principle.

Claims: Use of polymeric membranes in the dispensing of a pharmaceutical solution containing an active product, wherein at least one polymeric membrane is placed in a dropper portion of a dose dispenser housing said pharmaceutical solution, characterized in that said at least one polymeric membrane is used to permit the flow of essentially all of the active product and to retain essentially all of a preservative comprising a quaternary ammonium compound, during pharmacological treatment with said pharmaceutical solution. Use according to claim 1, wherein the polymeric membrane is a membrane of cellulose triacetate. Use according to claim 1, wherein the polymeric membrane is a membrane of cellulose nitrate. Use according to claim 1, wherein the polymeric membrane is a membrane of regenerated cellulose. Use according to claim 1, wherein the polymeric membrane is a membrane of nylon. Use according to claim 1, wherein the polymeric membrane is a membrane of polyvinylidene flouride. Use according to claim 1, wherein the polymeric membrane is a membrane of silicone. Use according to claim 1, wherein the polymeric membrane is a membrane of polysulfone. Use according to claim 1, wherein the polymeric membrane is a membrane of polycarbonate. Dose dispenser for pharmaceutical solutions comprising: a container (1) of a material easily deformable by pressure; a thread cap (2,16) with its corresponding sealing ring; and a dropper having a bottom part (3,10) and a top part (4,15) between which at least one polymeric membrane (5,18) is housed, the bottom part including a first cylinder unit (6) and the top part including a second cylinder unit (7) disposed such that said cylinder units (6,7) may come in contact with said at least one polymeric membrane (5,18); characterized that there is sufficient free space between said first cylinder unit (6) and said second cylinder unit (7), in order to allow for movement of said at least one polymeric membrane (5,18) between an upper position and a lower position, wherein in the lower position air is permitted to flow around the membrane and into the container. Dose dispenser according to claim 10, wherein the cylinder units (6,7) represent projections (19) which establish ducts that permit the pharmaceutical solution to pass from an axial hole (22) of the bottom part (10), the bottom part (10) of the dropper including a flap (11) for immobilization of said part on the outside of a neck (12) of the container (1), by insertion or optionally by thread, permitting the increase of the diameter of the at least one polymeric membrane (18) and therefore of the surface of the projections (19) that support said at least one membrane (18), making the surface of the membrane larger than the cross section area of the mouth and neck of the container (1), the bottom part (10) further including a sealing ring (13). Dose dispenser according to claim 11, wherein the projections (19) are embodied by a plurality of cylinder-like projections disposed in a concentric annular alignment and, in the center portion of the top part as well as of the bottom part, small disks (24) situated over the axial hole (22), acting as deflecting elements in order to avoid deformation of the membrane in that area. Dose dispenser according to claim 11, wherein the projections (19) comprise concentric annular partitions establishing chambers, there being radial or diametric cuts in said partitions in order to provide for fluid communication between said chambers, allowing a good dispersion of flow through the entire surface of the at least one polymeric membrane (18), there being a small wall (24) of cover of the innermost discontinuous annular partition, in order to prevent the membrane from wear or from breaking. Dose dispenser according to any of claims 11-13, characterized in that the top part (15) includes a thread (17) and immobilization means for the sealing ring (25) of the cover (16). Dose dispenser according to any of claims 10-14, wherein the at least one polymeric membrane includes a membrane of cellulose triacetate. Dose dispenser according to any of claims 10-14, wherein the at least one polymeric membrane includes a membrane of cellulose nitrate. Dose dispenser according to any of claims 10-14, wherein the at least one polymeric membrane includes a membrane of regenerated cellulose. Dose dispenser according to any of claims 10-14, wherein the at least one polymeric membrane includes a membrane of nylon. Dose dispenser according to any of claims 10-14, wherein the at least one polymeric membrane includes a membrane of polyvinylidene flouride. Dose dispenser according to any of claims 10-14, wherein the at least one polymeric membrane includes a membrane of silicone. Dose dispenser according to any of claims 10-14, wherein the at least one polymeric membrane includes a membrane of polysulfone. Dose dispenser according to any of claims 10-14, wherein the at least one polymeric membrane includes a membrane of polycarbonate.

Inventors: GIMENEZ GUASCH FRANCESC XAVIER, VALLET MAS ALBERTO, GIMENEZ GUASCH, FRANCESC XAVIER, VALLET MAS, ALBERTO
Applicants: ALCON CUSI S A, ALCON CUSI, S.A.
Application year: 1994
Main classification: A61J1
IPC codes: A61J3, C08L77, C08L69, C08L27, C08L81, A61J1